Artemisinin is a sesquiterpene lactone isolated from the plant Artemisia annua L, extracts of which has been used to treat malaria for at least 1600 years. The artemisinin molecule contains an endoperoxide bridge that reacts with an iron atom to form free radicals. The anti-malarial action of artemisinin is due to its reaction with intra-parasitic heme to generate free radicals, causing cell death. Cancer cells have a significantly higher influx of iron than normal cells. Accordingly, it has been shown that artemisinin and artemisinin analogs are cytotoxic against established tumors and tumor cell lines (see, e.g., Woerdenbag et al. (1993) J. Nat. Prod. 56(6):849-56; Lai & Singh (1995) Cancer Lett. 91:41-6; Efferth et al. (2001) Int. J. Oncol. 18:767-73; Li et al. (2001) Bioorg. Med. Chem. Lett. 11:5-8; Singh & Lai (2001) Life Sci. 70:49-56; Efferth et al. (2002) Biochem. Pharmacol. 64:617-23; Efferth et al. (2002) Blood Cells, Molecules & Diseases 28(2):160-8; Sadava et al. (2002) Cancer Lett. 179:151-6).
Many analogs of artemisinin and other compounds containing an endoperoxide bridge that are biologically active have been described (see, e.g., U.S. Pat. No. 5,180,840; U.S. Pat. No. 5,216,175; U.S. Pat. No. 5,225,427; Cumming et al. (1998) J. Med. Chem. 41(6):952-64; Posner et al. (1999) J. Med. Chem. 42:300-4; Li et al. (2001) Bioorg. Med. Chem. Lett. 11:5-8; Wu et al. (2001) Eur. J. Med. Chem. 36:469-79; Posner et al. (2003) J. Med Chem 46:1060-5). Analogs of artemisinin that have been used in the treatment of malaria include dihydroartemisinin, artemether, artesunate, arteether, propylcarbonate dihydroartemisinin and artelinic acid.
Artemisinin is a relatively safe drug with few and minor side effects even at high doses. Oral doses of 70 mg/kg/day for 6 days has been used in humans for malaria treatment. No apparent adverse side effects were observed after treatment of a cancer patient with artesunate (oral dose of 50 mg per day; intramuscular dose of 60 mg/day, for a period of 9 months) (Singh & Verma (2002) Arch. Oncol. 10(4):279-80). Artemisinin and artemisinin analogs have also been used in the treatment of skin conditions such as psoriasis, blistering skin diseases, viral warts, mulluscum contagiosum, and hemorrhoids (see, e.g., U.S. Pat. No. 4,978,676; U.S. Pat. No. 5,219,880). Artemisinin and artemisinin analogs have also been used for malaria prophylaxis.
It has been shown that administration of iron salts or the iron-carrying protein holotransferrin increases the susceptibility of cancer cells and implanted tumors to artemisinin and its analogs (Lai & Singh (1995) Cancer Lett. 91:41-46; Moore et al. (1995) Cancer Lett. 98:83-7; Singh & Lai (2001) Life Sci. 70:49-56; Sadava et al. (2002) Cancer Lett. 1179:151-6).
It has also been shown that certain pathogens obtain iron by binding to iron-carrying host proteins. For example, Neisseria meningitidis, the causative agent of bacterial meningitis, expresses cell surface receptors for iron-carrying compounds such as transferrin and lactoferrin (Evans & Oakhill (2002) Biochem. Soc. Trans. 30(4):705-7). Currently, no vaccine is available for the B strain of N. meningitidis, the most prevalent strain in the Western world. Furthermore, it has been shown that Helicobacter pylori, the etiologic agent of gastritis, gastric and duodenal ulcers, and adenocarcinoma in humans, obtains iron by binding human lactoferrin (Husson et al. (1993) Infect. Immun. 61 (6):2694-7).
There is a need in the art for artemisinin compositions with increased efficacy for the treatment of cancer and disease caused by pathogens that bind iron-carrying host proteins. There is also a need for methods for treating cancer and infections caused by pathogens that obtain iron by internalizing iron-carrying host proteins. The present invention addresses these needs.